BACKGROUND: Craniospinal irradiation (CSI) is the standard radiation therapy treatment for medulloblastoma. The aim of this study was to estimate and compare the lifetime risk of radiation-induced secondary cancer in pediatric medulloblastoma patients using three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: 3D-CRT and IMRT plans were performed for 10 CSI pediatric patients. The average absorbed doses for organs at risk (OARs) was calculated from dose-volume histograms on the treatment planning system. The average lifetime risk of radiation-induced secondary cancer was then calculated. RESULTS: Lifetime risk of secondary cancer for CSI pediatric patients treated using IMRT decreases in some OARs compared with those treated using 3D-CRT. This is attributable to the decrease in the average absorbed dose in some OARs when using IMRT technique. CONCLUSION: Follow-up of medulloblastoma pediatric patients should be performed after ending the treatment course in order to diagnose early secondary tumors. IMRT technique is substantially better than 3D-CRT in terms of lifetime risk of radiation-induced secondary cancer, probably due to reduced dose to OARs especially to the thyroid, which is the most sensitive organ to radiation.

How to cite this article:Sherif RS, Elshemey WM, Attalla EM. The risk of secondary cancer in pediatric medulloblastoma patients due to three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. Indian J Cancer 2018;55:372-6

How to cite this URL:Sherif RS, Elshemey WM, Attalla EM. The risk of secondary cancer in pediatric medulloblastoma patients due to three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. Indian J Cancer [serial online] 2018 [cited 2019 May 25];55:372-6. Available from: http://www.indianjcancer.com/text.asp?2018/55/4/372/253293

» Introduction

Medulloblastoma is considered as one of the most common pediatric tumors of the central nervous system (CNS).[1] Craniospinal irradiation (CSI) is an important radiotherapy technique to control the cancer of the CNS.[2] Most of the patients requiring CSI treatment are children,[3],[4] so it is very important to study the long-term effects of cancer treatment. Developing a second cancer is one of the most serious possible late complications of cancer treatment. The risk of developing secondary cancer is greatly associated with the age of the patient at the time of exposure to radiotherapy.[5],[6],[7],[8] Pediatric patients are associated with an increased risk of a secondary cancer compared to adults.[9],[10],[11],[12],[13]

Three-dimensional conformal radiotherapy (3D-CRT) is the main radiotherapy technique used for the treatment of medulloblastoma in pediatric patients in some treatment centers worldwide.[14] Patients are treated in the supine position and carefully the junctions developed between opposed lateral cranial fields and a posterior spinal field are taken into consideration. It is a fact that in 3D-CRT large areas of normal tissue and organs at risk (OARs) nearer to the target receive considerable dose of radiation.[15],[16],[17],[18],[19] On the contrary, intensity-modulated radiotherapy (IMRT) technique increases the ability to maximize the dose to the tumor and spare normal tissues. Unfortunately, it may increase the risk of secondary cancers due to radiation leakage from the linear accelerator due to the increase in the number of beams and the number of monitor units (MUs).[3] Hall and Wuu [20] reported that IMRT may double the incidence of second malignancies compared with 3D-CRT. On the other hand, the results of Studenski et al.,[21] Brodin et al.,[22] and Suntornpong [23] suggest that IMRT potentially reduces the incidence of secondary cancer in pediatric patients.

Since 3D-CRT is routinely used for the treatment of pediatric medulloblastoma patients in some treatment centers worldwide,[14] it is extremely important to calculate the lifetime risk of secondary cancer for those patients to figure out if they are possibly facing higher lifetime risk compared with those treated using IMRT as reported by some of the previous studies.[20],[21],[22],[23]

» Materials and Methods

Patients and treatment planning

Ten pediatric patients of ages between 7 and 13 years undergoing CSI as a part of treatment of medulloblastoma were chosen for this study.

Treatment was carried out using 3D-CRT in the supine position with the help of treatment plans performed on Elekta Monaco version 5.11 treatment planning system (Elekta CMS, Maryland Heights, MO) employing a collapsed cone algorithm.

Two opposed lateral cranial fields (gantry angles of 90° and 270° with collimator angles of 10° and 170°) were used for photon treatment plans in addition to one direct posterior spinal field (gantry angle of 180°) or, in some cases, two posterior oblique spinal fields (gantry angles of 160° and 200°) based on the case under treatment. Photon fields of 6 MV were used.

A radiation oncologist carried out the delineation of OARs (thyroid, lungs, stomach, liver, bladder, kidneys, and eyes) on the planning computed tomography images of each patient.

The conventional radiotherapy prescription dose for the treatment of high-risk medulloblastoma (36 Gy delivered in 20 fractions of 1.8 Gy per fraction) was applied to the craniospinal target.

In order to compare the lifetime risk between IMRT and 3D-CRT in medulloblastoma pediatric patients, IMRT planning was performed on the same patients and compared with 3D-CRT. IMRT plans were carried out on Elekta Monaco version 5.11 (Elekta CMS) with Monte Carlo algorithm at gantry angles of 180°, 240°, 310°, 50°, and 120° for cranium and spine.

The lifetime risk of radiation-induced secondary cancer after medulloblastoma treatment due to 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy

To calculate the risk of induced secondary cancer for the OARs, the equivalent dose for these organs should be first calculated using the following equation:[24]

ET = DT × WR(1)

Where ET is the equivalent dose of organ T in Sv, DT is the mean absorbed dose by organ T, and WR is the radiation weighting factor which is equal to 1 for photons.

The lifetime risk of radiation-induced secondary cancer for all OARs was calculated (except for the kidneys and eyes, as there are no nominal risk coefficients [NRC] data available for such organs) using the values of NRCs from ICRP Publication 103[24] given by the following equation [25]:

Risk of radiation-induced secondary cancer (%) = ET × NRC.(2)

Statistical analysis

The mean and standard deviation values were calculated with the help of Microsoft Excel 2007. Duncan multiple range test (in SPSS 19 statistics software (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp) package) was used to calculate the statistical significance of data.

» Results

Absorbed dose in organs at risks due to 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy

[Figure 1] shows a comparison between the average absorbed dose of OARs (thyroid, right lung, left lung, stomach, liver, bladder, right kidney, left kidney, right eye, and left eye) calculated for 3D-CRT and IMRT. The average absorbed dose for thyroid, stomach, liver, right eye, and left eye is significantly (P < 0.05) lower for patients treated using IMRT (16.70 ± 1.8, 8.50 ± 0.6, 6.78 ± 0.5, 26.90 ± 0.3, and 28.00 ± 0.2 Gy, respectively) compared with those treated using 3D-CRT (30.00 ± 0.6, 10.6 ± 0.9, 8.58 ± 1.0, 33.00 ± 1.0, and 32.94 ± 0.7 Gy, respectively). On the other hand, the average absorbed dose for left lung and bladder is significantly (P < 0.05) higher for patients treated using IMRT compared with those treated using 3D-CRT. The maximum difference in absorbed dose among all OARs between the two techniques is reported for thyroid.

Figure 1: Average absorbed dose of organs at risks for 10 medulloblastoma pediatric patients for 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy. The error bars represent the standard deviation from mean

[Figure 2] shows a comparison between the average lifetime risk of radiation-induced secondary cancer of some OARs (thyroid, right lung, left lung, stomach, liver, and bladder) due to 3D-CRT and IMRT as calculated using the equation 2. The average lifetime risk of radiation-induced secondary cancer for thyroid, stomach, and liver is significantly (P < 0.05) lower for patients treated using IMRT (5.50 ± 0.6%, 6.70 ± 0.5%, and 2.00 ± 0.1%, respectively) compared with those treated using 3D-CRT (9.90 ± 0.2%, 8.40 ± 0.7%, and 2.6 ± 0.3%, respectively). On the other side, the average lifetime risk of radiation-induced secondary cancer for left lung and bladder is significantly (P < 0.05) higher for patients treated using IMRT compared with those treated using 3D-CRT. This is attributable to the higher average absorbed dose in these two OARs (left lung and bladder) for patients treated using IMRT compared with those treated using 3D-CRT.

Figure 2: Average lifetime risk of induced secondary cancer in various organs at risks for 10 medulloblastoma pediatric patients for 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy. The error bars represent the standard deviation from mean

Children are more susceptible to the risk of radiation-induced secondary cancers than adults due to the radiation sensitivity of their organs and tissues, the proximity of OARs and normal tissues to the treatment fields, the continuing development of their organs, and that they may survive several years after the treatment of the primary cancer.[26],[27],[28] Therefore, calculating the lifetime risk of radiation-induced secondary cancer is very important to understand whether the 3D-CRT technique that is routinely used in some treatment centers worldwide may be causing increased risk of radiation-induced secondary cancer that should be avoided.

Lee et al.[29] described the incidence and characteristics of secondary malignant neoplasms (SMNs) in adolescent and young adult cancer survivors compared with those in younger and older cancer survivors. They concluded that adolescent and young adults who survive after cancer treatment for more than 5 years have a higher relative risk of SMN compared with the general population and have a higher absolute risk of SMN compared with younger or older cancer survivors.

Stavrou et al.[30] also reported a significant increase in subsequent cancer with 4 of 88 patients diagnosed with secondary cancer within 10 years after radiation treatment.

According to a linear dose–response model, a general reduction in absorbed doses (reflected by mean dose to OARs) should be the aim in order to decrease the risk of radiation-induced secondary cancer.[2]

The present results show a significant decrease in the average absorbed dose (mean dose) for some OARs (thyroid, stomach, liver, and eyes) for patients treated using IMRT compared with those treated using 3D-CRT. These results agree with Studenski et al.[21] who compared the dosimetric advantages of IMRT and volumetric-modulated arc therapy (VMAT) with 3D-CRT planning in CSI patients for both cranial and spine fields. They reported that IMRT decreases the dose for OARs (thyroid, stomach, liver, small bowel, heart, esophagus, lungs, and kidneys) compared with each of VMAT or 3D-CRT.

Several models were presented by ICRP to predict the risk of radiation-induced cancer for radiotherapy doses based on the linear approximation of the risks of the atomic bomb survivors using the effective dose (the tissue-weighted sum of the equivalent doses in all specified tissues) for risk estimation. For fractionated dose, basic risk factors are usually modified by a dose and dose-rate effectiveness factor (DDREF, the ratio between the risk per unit effective dose for high dose rates and that for low dose rates).[31] If DDREF value of two is used when dealing with a fractionated dose,[25],[32] the risk of radiation-induced secondary cancer is expected to decrease to one-half of the values presented in [Figure 2], but still the difference between the risk of secondary cancer between IMRT and 3D-CRT remains the same.

Rehman et al.[33] evaluated the lifetime risk of secondary cancer from IMRT and 3D-CRT for spine radiotherapy. Their results indicated that IMRT had lower lifetime risk of secondary cancer than 3D-CRT for OARs (esophagus, lung, and bone surface).

Ardenfors et al.[34] compared the risk of radiation-induced secondary cancer for head and neck tumors due to IMRT and 3D-CRT. Their results indicated that the redistribution of the dose due to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques.

Elgendy et al.[35] evaluated the risk of secondary cancer in 3D-CRT and IMRT for the infield and out-of-field organs from the primary radiation fields. Their results showed increase in dose for out-of-field OARs with IMRT plan compared with 3D-CRT, where in IMRT larger volume is irradiated to lower doses. This is because the total MUs in IMRT are higher than in 3D-CRT which increases the probability of induction of a second primary cancer in out-of-field OARs in IMRT than in 3D-CRT. The infield OARs receive lower doses with IMRT allowing significant reduction in the doses to infield OARs compared with 3D-CRT.

Contrary to the results by many authors (shown above), which all confirm that the lifetime risk associated with IMRT is considerably lower than 3D-CRT, Hall and Wuu [20] reported that IMRT may double the incidence of second malignancies compared with 3D-CRT.

Despite the fact that IMRT has been reported by several authors (including this study) to have lower lifetime risk compared with 3D-CRT, the latter has been reported by many authors to show lower lifetime risk compared with a number of advanced techniques.

Previous studies showed that the risk of radiation-induced secondary cancer in CSI patients, especially in the breast and lung, was higher in the case of tomotherapy (TOMO) compared with 3D-CRT.[11],[12],[36],[37],[38],[39] Holmes et al.[39] showed that in addition to the breast and lung, they found a significant increase in the risk of colorectal cancer using TOMO CSI compared with 3D-CRT.

Myers et al.[37] made a comparison among TOMO, VMAT, and 3D-CRT for CSI. They found that 3D-CRT plans had the lowest mean dose values compared with TOMO or VMAT.

Zhang et al.[1] compared proton and photon therapies in terms of the predicted risk of second cancers for a 4-year-old male medulloblastoma patient receiving CSI. They found that proton therapy conferred lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient. Athar and Paganetti [40] compared 6-MV IMRT and proton therapy in terms of organ-specific second cancer lifetime attributable risks caused by scattered and secondary out-of-field radiation. They found that for out-of-field risks, IMRT offered advantage close to the primary field. An increasing advantage for passive proton therapy was noticed with increasing distance to the field.

Yoon et al.[36] evaluated the dosimetric benefits of advanced radiotherapy techniques (3D-CRT, TOMO, and proton beam treatment [PBT]) for CSI in pediatric patients. Dosimetric benefits and organ-specific radiation-induced cancer risks were based on comparisons of dose-volume histograms and on the application of organ equivalent doses (OEDs), respectively. They found that PBT showed improvements in most dosimetric parameters for CSI patients, with lower OEDs to OARs compared with photon techniques. Eaton et al.[41] compared the long-term disease control and overall survival between children treated with proton and photon radiotherapies for standard risk medulloblastoma. They found that disease control with proton and photon radiotherapy appeared equivalent for standard risk medulloblastoma.

Kirsch and Tarbell [42] compared the long-term side effects of treatment due to high-energy X-rays (photons) and proton radiation therapy for children with brain tumors. They suggested that proton beam radiation therapy might limit the late effects of radiation therapy and therefore offer an advantage over techniques using photons. Yuh et al.[43] reported that proton beam technique for CSI of pediatric medulloblastoma had successfully reduced normal tissue doses and acute treatment-related sequelae. They added that this technique might be especially advantageous in children with a history of myelosuppression, who might not otherwise tolerate irradiation.

St. Clair et al.[44] compared treatment plans from standard photon therapy, intensity-modulated X-rays (IMRT), and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. Their study demonstrated the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared with conventional X-rays. They added that between the two conformal treatment methods evaluated, protons were found to be superior to IMRT. Newhauser et al.[45] compared the risk of developing a second cancer after CSI using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Simulations revealed that both passively scattered and scanned beam proton therapies conferred significantly lower risks of second cancers than 6-MV conventional and intensity-modulated (IM) photon therapies.

Miralbell et al.[11] assessed the potential influence of improved dose distribution with proton beams compared with conventional or IM X-ray beams on the incidence of treatment-induced secondary cancers in medulloblastoma pediatric patient. They found that proton beams reduced the expected incidence of radiation-induced secondary cancers in the medulloblastoma case by a factor of 8–15 when compared with either IM or conventional X-ray plans.

» Conclusion

Follow-up of pediatric medulloblastoma patients is recommended after the course of their treatment in order to diagnose any secondary cancer at early stages. IMRT technique is recommended in the treatment of medulloblastoma pediatric patients compared with 3D-CRT as it can reduce the dose and consequently the lifetime risk of radiation-induced secondary cancer in some OARs which include the most radiosensitive organ (thyroid). This is very important for pediatric patients because they are more susceptible to the risk of radiation-induced secondary cancer than adults as they are expected to survive several decades after the radiation treatment. It is important to consider the use of proton therapy when available as there is evidence in literature that it may probably offer reduced lifetime risk of radiation-induced secondary cancer compared with the discussed techniques.